Lactate oxidase-engineered manganese layered double hydroxide nanoplatform amplifies cGAS-STING activation for tumor immunotherapy.

Authors

Feng Cai, Dengsheng Jiang, Mingzhe Geng, Hongbo Xu, Shilong Song, Gengming Wang, Zelai He, Lu Xu

Published in

International journal of biological macromolecules. Pages 153862. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

The cGAS-STING pathway plays a central role in antitumor innate immunity, but the therapeutic efficacy of STING agonists is often limited by insufficient tumor delivery and inadequate amplification of endogenous danger signals. Here, we developed a lactate oxidase-engineered manganese layered double hydroxide nanoplatform loaded with the STING agonist MSA-2, termed Mn-LDH-M@LOX, to establish a tumor metabolism-driven STING amplification strategy. Under mildly acidic tumor-associated conditions, Mn-LDH-M@LOX underwent structural disassembly and synchronously released manganese ions and MSA-2. Meanwhile, surface-immobilized LOX converted tumor-derived lactate into hydrogen peroxide, thereby providing an endogenous fuel for manganese-mediated ROS amplification. This cascade induced oxidative DNA damage, mitochondrial dysfunction and cytosolic mtDNA accumulation, which further reinforced cGAS-STING-related immune activation together with MSA-2 and manganese ions. In 4T1 tumor cells, Mn-LDH-M@LOX efficiently enhanced ROS generation, mitochondrial depolarization, γ-H2AX-associated DNA damage, ICD-related signals and downstream immune responses, including increased p-IRF3, IFN-β and CXCL10. In vivo, Mn-LDH-M@LOX significantly suppressed tumor growth, reduced intratumoral lactate content and decreased Ki67 expression, while promoting CRT exposure, dendritic cell maturation, CD4⁺/CD8⁺ T-cell infiltration and intratumoral cytokine/chemokine production. Moreover, no obvious systemic toxicity was observed based on body weight, blood biochemical indices, routine blood parameters and major organ histology. Overall, this work presents a lactate-fueled manganese nanocatalytic platform that converts tumor metabolic reprogramming into ROS-amplified STING activation, offering a promising strategy for enhanced tumor immunotherapy.

PMID:
42600811
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.